In Utero Valproic Acid Exposure in Cryptorchidism Reports: Integrating FAERS, Toxicogenomics, Transcriptomics, and Mendelian Randomization.

Abstract

To screen the FDA Adverse Event Reporting System (FAERS) for valproic acid (VPA)-associated cryptorchidism reports, restrict developmental interpretation to documented transplacental/in utero exposure, and prioritize candidate genes without claiming mechanistic validation, we analyzed 7,232 deduplicated primary-suspect VPA reports in males aged ≤18 years from 2004Q1-2025Q4. Cryptorchidism screening identified 108 reports; exposure-route review defined the prenatal subset. Disproportionality analyses used pediatric male FAERS reports with primary-suspect drugs as the background. Curated human VPA-associated genes from the Comparative Toxicogenomics Database (CTD) were intersected with differentially expressed genes from cryptorchidism testicular tissue (GSE16191). The 21 shared genes underwent two-sample Mendelian randomization (MR) using GTEx v8 testis eQTL instruments and FinnGen cryptorchidism data (261 cases and 374,410 controls). Exposure route was available for 104 reports; 93 (89.42%) documented transplacental/in utero exposure, whereas 11 other/non-in utero reports and four reports with missing route information were excluded from developmental interpretation. GPX7 and PLCL1 showed nominal inverse-variance-weighted associations, but neither survived Benjamini-Hochberg correction (both q = 0.399) or Bonferroni correction (adjusted p = 0.693 and 0.798, respectively). ACYP2 showed a borderline inverse association. Sensitivity estimators did not consistently support these signals. FAERS identified a VPA-cryptorchidism reporting signal, but cannot estimate incidence or establish causality. Prenatal interpretation was limited to 93 in utero reports. The integrated CTD, transcriptomic, and MR findings support exploratory candidate prioritization rather than a validated causal or mechanistic chain.